Oncoviruses and innate immunity

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Projects and grants

Overall, short, medium, and long-term goals
The main research of the innate immunity and cancer team will initially continue using the same strategies adopted in the past years.

The molecular mechanisms responsible for TLR9 deregulation by HBV

WHO estimates that about 2 billion people are infected with hepatitis B virus (HBV) in the world and that 400 million become chronic carriers who are then at high risk of developing liver cirrhosis and hepatocellular carcinoma. Our preliminary results indicate the presence of CpG motifs derived within the viral genome of HBV which are capable to activate TLR9 (Vincent et al PloS One., 2011). Furthermore, we showed that HBV infection of peripheral blood mononuclear cells (PBMC) led to the deregulation of TLR9 by blocking the secretion of interferon I type. Thus, it is possible that HBV can be recognized by TLR9, but later denied any new viral recognition by blocking is function. We plan to dissect the molecular mechanisms responsible for the deregulation of TLR9 by HBV using similar strategies described in our publications Hasan et al JI ., 2007 and JEM 2013.

The role of TLR9 on the cell cycle in cancer

TLR9 recognizes double-stranded DNA in the form of non-methylated CpG motifs found in bacterial and viral genomes which permit the production of type I IFN and proinflammatory cytokines. In humans, TLR9 is expressed by immune cells such as pDCs and B cells, but some reports have detected the presence of TLR9 also by epithelial and endothelial cells. Recently, we showed in parallel with other laboratories that HPV16, EBV and HBV were able to alter the expression and function of TLR9. Over expression of TLR9 (with an exogenous promoter), in cells infected with EBV or HPV16, decreased their ability to proliferate. Thus, in addition to its role in innate immunity, TLR9 can control events that promote the transformation of epithelial cells or cell growth by itself. Our goal is to understand the physiological consequences TLR9 expression in the context of transformation and / or proliferation of epithelial cells. We aim to determine the mechanisms and physiological consequences of TLR9 function before and during cancer development.

Regulation of the inflammasome by the human papillomavirus type 16

The human papillomavirus (HPV) high-risk mucosal types are the causative agents of cervical cancer. The development of cancers induced by HPV, particularly HPV16, is intimately linked to the persistence and progression of viral infection. The inflammasome is responsible for the activation of inflammatory processing of IL-1B and IL-18 and has been shown to induce a cellular pyroptosis, a process of programmed cell death distinct from apoptosis. AIM2 (absent in melanoma 2), a family member AIM2 HIN-200, was recently identified as a cytosolic receptor for DNA sequences and activates the inflammasome. It recognizes poly (dA-dT) sequences found in vaccinia virus, allowing secretion of IL-1B and cell death. It is therefore possible that: 1.Other double-stranded DNA viruses can be detected by the innate immune response have not been discovered yet and 2. That oncoviruses have developed strategies to avoid immune recognition. We have preliminary data showing the loss of IL-1B in cells transduced with HPV16 E6/E7 oncoproteins compared with normal primary keratinocytes. Protein levels of the pro-form of IL-1B are reduced in human keratinocytes expressing the viral oncoproteins. To date, nothing is known about the expression of inflammasome in keratinocytes and its deregulation and / or activation possible by HPV16. In this program our objectives are to identify i) the role of HPV16 in regulating the pro-form of IL-1B in the context of a response from the inflammasome and ii) the regulation of the expression of AIM2, a candidate to sense HPV16 infection.

The molecular events responsible for the deregulation of AIM2-by HBV

HBV is widely regarded as a “stealth” virus not triggering innate immune responses. However, this notion is challenged by recent studies, we have data using primary cultures of human hepatocytes and Kupffer cells (cells of the liver) produce IL-1β in response to inflammasome ligands. To date, nothing is known about the expression of the inflammasome by liver cells and its possible activation/deregulation by HBV. Using primary human hepatocytes (PHH), Kupffer cells (liver macrophages) and liver progenitor cells (HepaRG cells), we wish to analyze the potential activation and the role of the inflammasome during HBV infection. This project should provide new data on the innate immune response of the liver and its potential role in the control of HBV replication. This knowledge could have important clinical implications for the development of new immunotherapeutic approaches.